Trial Information

High Risk Neuroblastoma Study 1 Of Siop-Europe

OBJECTIVES:

- Compare the efficacy of myeloablative therapy with busulfan and melphalan vs
carboplatin, etoposide, and melphalan, in terms of 3- and 5-year event-free survival
(EFS), progression-free survival (PFS), and overall survival (OS), in patients with
high-risk neuroblastoma.

- Compare the 3-year EFS in these patients treated with isotretinoin with or without
monoclonal antibody Ch14.18 after myeloablative therapy.

- Determine the response at metastatic sites after induction chemotherapy in these
patients.

- Determine the effect of metastatic disease response after induction chemotherapy on
EFS, PFS, and OS in these patients.

- Compare the toxicity and episodes of febrile neutropenia in patients treated with
induction chemotherapy with or without filgrastim (G-CSF).

- Determine the effect of elective hematopoietic support with G-CSF during induction
chemotherapy on peripheral blood stem cell collection in these patients.

- Compare the acute and long-term toxic effects of the 2 myeloablative therapy regimens
in these patients.

- Determine the effect of radiotherapy on pre-surgical tumor volume at the primary site
on local control, EFS, PFS, and OS in these patients.

- Determine the tolerability of isotretinoin with or without monoclonal antibody Ch14.18
after myeloablative therapy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
disease stage (2 or 3 with MycN amplification vs 4). Patients are randomized to 1 of 8
treatment arms:

Arm I:

- Patients receive induction chemotherapy comprising vincristine IV, carboplatin IV over
1 hour, and etoposide IV over 4 hours on days 1 and 41; vincristine IV and cisplatin IV
over 24 hours on days 11, 31, 51, and 71; and vincristine IV on days 21 and 61 and
cyclophosphamide IV and etoposide over 4 hours on days 21, 22, 61, and 62. Patients
receive filgrastim (G-CSF) subcutaneously on days 3-8, 12-18, 23-28, 32-38, 43-48,
52-58, 63-68, and 72 until peripheral blood stem cell (PBSC) collection.

- Patients undergo PBSC collection beginning on day 80. Patients then undergo surgery on
day 95.

- Patients receive myeloablative therapy comprising oral busulfan 4 times daily on days
-6 to -3 and melphalan IV over 15 minutes on day -2. Patients undergo PBSC infusion on
day 0.

- Patients undergo radiotherapy in 14 fractions over 21 days.

- Beginning within 30 days after radiotherapy, patients receive oral isotretinoin twice
daily on days 1-14. Treatment repeats every 28 days for 6 courses.

Arm II:

- Patients receive induction chemotherapy as in arm I, but with no G-CSF. Patients then
undergo PBSC collection and surgery as in arm I. Patients receive myeloablative therapy
and undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I.

- Patients receive oral isotretinoin twice daily on days 1-14 and monoclonal antibody
Ch14.18 IV over 8 hours on days 1-5. Treatment repeats every 28 days for 6 courses for
isotretinoin and every 28 days for 5 courses for monoclonal antibody Ch14.18.

Arm III:

- Patients receive induction chemotherapy and G-CSF as in arm I. Patients then undergo
PBSC collection and surgery as in arm I. Patients receive myeloablative therapy and
undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I. Patients
receive isotretinoin as in arm I.

Arm IV:

- Patients receive induction chemotherapy as in arm II. Patients then undergo PBSC
collection and surgery as in arm I. Patients receive myeloablative therapy and undergo
PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I. Patients receive
isotretinoin and monoclonal antibody Ch14.18 as in arm II.

Arm V:

- Patients receive induction chemotherapy and G-CSF as in arm I.

- Patients receive myeloablative therapy comprising carboplatin IV continuously and
etoposide IV continuously on days -7 to -4 and melphalan IV over 15 minutes on days -7
to -5. Patients undergo PBSC infusion on day 0.

- Patients undergo radiotherapy as in arm I. Patients receive isotretinoin as in arm I.

Arm VI:

- Patients receive induction chemotherapy as in arm II. Patients receive myeloablative
therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm
I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II.

Arm VII:

- Patients receive induction chemotherapy and G-CSF as in arm I. Patients receive
myeloablative therapy and undergo PBSC infusion as in arm V. Patients undergo
radiotherapy as in arm I. Patients receive isotretinoin as in arm I.

Arm VIII:

- Patients receive induction chemotherapy as in arm II. Patients receive myeloablative
therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm
I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II.

Patients on all treatment arms are followed every 6 months for 3 years and then annually for
2 years.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: Approximately 175 patients per year will be accrued for this study.